Incidence of laboratory-confirmed influenza and RSV and associated presenteeism and absenteeism among healthcare personnel, Israel, influenza seasons 2016 to 2019

Background Healthcare personnel (HCP) are at high risk for respiratory infections through occupational exposure to respiratory viruses. Aim We used data from a prospective influenza vaccine effectiveness study in HCP to quantify the incidence of acute respiratory infections (ARI) and their associated presenteeism and absenteeism. Methods At the start and end of each season, HCP at two Israeli hospitals provided serum to screen for antibodies to influenza virus using the haemagglutination inhibition assay. During the season, active monitoring for the development of ARI symptoms was conducted twice a week by RT-PCR testing of nasal swabs for influenza and respiratory syncytial virus (RSV). Workplace presenteeism and absenteeism were documented. We calculated incidences of influenza- and RSV-associated ARI and applied sampling weights to make estimates representative of the source population. Results The median age of 2,505 participating HCP was 41 years, and 70% were female. Incidence was 9.1 per 100 person-seasons (95% CI: 5.8–14.2) for RT-PCR-confirmed influenza and 2.5 per 100 person-seasons (95% CI: 0.9–7.1) for RSV illness. Each season, 18–23% of unvaccinated and influenza-negative HCP seroconverted. The incidence of seroconversion or RT-PCR-confirmed influenza was 27.5 per 100 person-seasons (95% CI: 17.8–42.5). Work during illness occurred in 92% (95% CI: 91–93) of ARI episodes, absence from work in 38% (95% CI: 36–40). Conclusion Influenza virus and RSV infections and associated presenteeism and absenteeism were common among HCP. Improving vaccination uptake among HCP, infection control, and encouraging sick HCP to stay home are important strategies to reduce ARI incidence and decrease the risk of in-hospital transmission.


Background
While it is useful to know the incidence of influenza and respiratory syncytial virus (RSV)-associated acute respiratory illnesses (ARI) when assessing the costbenefit balance of vaccination, few countries have generated such findings for potential target groups such as healthcare personnel (HCP) [1].Compared with other community-dwelling adults, HCP are disproportionally exposed to respiratory viruses through work and are often at higher risk for infections [2].Workplace absenteeism, and associated costs of lost productivity among HCP, is also an important component of the financial burden to society and of potential utility when estimating costs and benefits of vaccination.
Better understanding the burden of influenza and RSV infections among HCP can inform prioritisation of public health resources, including influenza vaccination [3].In addition, while vaccine acceptance is critical to the success of influenza vaccination campaigns [4,5], HCP are often reluctant to use or recommend vaccines because of uncertainty about their risk of infection [6].Appreciation of influenza illness risk, for example, can motivate HCP to get vaccinated against influenza [7].
The incidence of influenza and RSV infection among children [8][9][10] and older adults [11,12], two populations prioritised for influenza vaccination, has been well quantified in Israel.While Israel also recommends seasonal influenza vaccines for HCP, little is known about HCP's risk of influenza and illness impact on presenteeism and absenteeism [13].We leveraged data from a prospective cohort study of influenza vaccine effectiveness among HCP in Israel [14] and quantified the incidence of all-cause ARI, influenza and RSV illnesses, as well as presenteeism and absenteeism associated with these illnesses.

Methods
During the 2016/17, 2017/18, and 2018/19 influenza seasons, HCP at the Soroka and Rabin Medical Centers in Israel were enrolled as described previously [14].Briefly, at the start of each season, HCP at both participating hospitals were enrolled in the study using a stratified random sampling approach across 36 strata of age, sex (binary: male or female) and occupation to improve representativeness.Following written informed consent, HCP completed an enrolment survey that included questions about sociodemographic and occupational characteristics.Data on pre-existing conditions and influenza vaccination were collected from electronic medical records and hospital employee vaccination registries.We considered HCP as vaccinated if they received their influenza vaccine at least 2 weeks before the peak of the influenza season.Participating HCP also provided serum specimens to screen for antibodies to influenza virus using the haemagglutination-inhibition (HI) assay at the start and end of each influenza season.Timing of each influenza season was determined by the first and last influenza virus infections detected in the cohort via RT-PCR: the epidemic period was epidemiological week W49 in 2016 through W11 in 2017 for 2016/17 season, W48 in 2017 through W12 in 2018 for the 2017/18 season, and W48 in 2018 through W10 in 2019 for the 2018/19 season.
During influenza seasons, enrolled HCP began active surveillance for development of ARI within the past 7 days [14].Participants received twice-weekly short message service (SMS) surveillance messages to report any ARI symptoms.If they did not respond to two consecutive messages, they received reminder calls from study staff.They were also encouraged to contact study staff directly if they experienced ARI symptoms.If the HCP reported symptoms, they had nasal swab samples collected by self-collection or study staff [15,16], and samples were tested for influenza and RSV ribonucleic acid by RT-PCR at the Soroka Hospital Laboratory.Symptomatic HCP completed a confidential questionnaire about whether they worked while ill with any ARI symptom (defined as presenteeism) or missed work because of illness (defined as absenteeism); questionnaire data were compared and reconciled with each hospital's human resources records.If HCP reported missed work, we recorded the number of hours missed, but the questionnaire did not capture the number of hours worked while ill.The HCP What did you want to address in this study and why?Seasonal influenza vaccination is widely recommended for healthcare personnel (HCP), but little is known about the risk of respiratory infections like influenza and respiratory syncytial virus (RSV) among HCP and about how respiratory illnesses contribute to absenteeism (missing work) and presenteeism (working while ill) among HCP.We undertook a study to answer these questions to help inform mitigation measures and return-to-work policies for HCP.

What have we learnt from this study?
Respiratory virus infections were common among HCP in two Israeli hospitals.Unvaccinated HCP had 9.1 influenza episodes per 100 people (on average across the three influenza seasons) confirmed through testing of nasal swabs.That rate more than doubled when we added infections identified through blood tests for antibodies.Most HCP worked at least 1 day while sick and workplace absenteeism resulted in more than 23,000 hours of lost work.

What are the implications of your findings for public health?
We found high incidence of acute respiratory illness (ARI), influenza and RSV infections and workplace presenteeism and absenteeism among HCP.Improving influenza vaccination coverage, considering the introduction of RSV vaccines, optimising infection control measures, and encouraging sick HCP to stay home are important strategies to reduce the burden of ARI, optimise healthcare system resilience and reduce healthcare-associated transmission.

KEY PUBLIC HEALTH MESSAGE
also self-rated their ability to do work activities during illness on a scale from 0 to 9, where 0 was inability to do any usual activity and 9 was ability to do all usual activities.This scale has previously been validated to evaluate the impact of acute respiratory illness on activities of daily living among HCP [17][18][19].
We defined ARI as an illness with at least one of the following symptoms: cough, feverishness (i.e.subjective or measured fever), rhinorrhoea or body aches, regardless of aetiology or severity [14].Illness duration was determined as the number of days between onset of the first symptom and complete symptom resolution.We considered reported ARI as separate episodes if more than 14 days had passed between symptom resolution of the preceding ARI and symptoms onset of the subsequent episode.If a person had two different infections with the same virus (e.g.influenza A and influenza B or influenza A(H3) and influenza A(H1N1)) in the same season, these were treated as two separate illnesses.Unvaccinated HCP who did not meet the ARI case definition but demonstrated serological evidence of natural infection were classified as having asymptomatic infections.Serological evidence of influenza infection was defined as a ≥ 4-fold rise in HI antibody titres from pre-to post-season serum samples (i.e.seroconversion) and a ≥ 1:40 HI titre on the post-season sample.Serology samples were not systematically tested for RSV.
Cumulative incidence of ARI, influenza-associated ARI and RSV-associated ARI was calculated by dividing the number of illness episodes by the number of study participants per influenza season (i.e. the proportion of people who develop an ARI during an influenza season) and is expressed as person-season.During missed surveillance weeks, HCP were assumed to be without illness.In addition, we calculated cumulative incidence of ARI-associated presenteeism and absenteeism by dividing the number of presenteeism or absenteeism  a Participants were excluded if they enrolled in the study but could not be reached ("missed surveillance") in any week of the influenza season.
Some participants were involved in multiple years.The totals per box refer to unique individuals involved in at least one of the three seasons.events during ARI episodes by the person-seasons.We applied sampling weights to generate incidence estimates representative of the source population (i.e.all HCP employed at Soroka or Rabin Medical Centers and members of Clalit Health Services).
To examine demographical or occupational [20] factors (e.g.differences in respiratory illness risk by ethnicity) associated with ARI, influenza-associated ARI and RSV-associated ARI incidence, we used Poisson regression to calculate relative risk.Generalised estimating equations (GEE) were used to account for repeated measures on HCP participating in multiple influenza seasons.In all adjusted models, we included sex, age, occupation and hospital in the model a priori to be consistent with a prior study in the same cohort [21].Variables of interest significantly associated with the ARI, influenza-associated ARI and/or RSV-associated ARI in the univariate Poisson regression were included in the multivariable models.We considered p values < 0.05 statistically significant.
Among ARI episodes, rates of presenteeism and absenteeism were calculated as the percentage of ARI episodes associated with presenteeism or absenteeism, and 95% Clopper-Pearson confidence intervals (CI) were estimated [13].We also calculated cumulative hours of missed work among all ARI episodes by summing the total number of scheduled work hours that participants missed during a period when they were sick with an ARI.The HCP were considered unable to do usual activities if they rated their ability to perform daily activities as 0-6, and able to do usual activities if they rated their ability to perform daily activities as 7-9.Like above, factors associated with presenteeismand absenteeism-related ARI episodes were assessed by univariate and multivariable logistic GEE.
We used multiple imputation by chained equations [22] to impute laboratory results for ARI without respiratory samples and to impute presenteeism and absenteeism from ARI without such information.The imputation models included the same variables as those in the analytic models and auxiliary variables that are either associated with the missing mechanism or correlated with the missing data.Twenty imputed datasets were generated, and parameter estimates from each dataset were pooled to obtain summary metrics for analyses.Finally, we conducted sensitivity analyses that used person-time as the denominator when calculating relative rates to examine how accounting for person-time accrual might affect the findings.An HCP accrued person-time at risk during weeks when influenza virus was detectable in the cohort across three influenza seasons.The duration of ARI and a 14-day post-ARI refractory period were subtracted from person-time calculations overall for any ARI and separately by viral aetiology.We used Poisson GEE with person-time as an offset term to calculate relative rate.We also conducted sensitivity analyses including both complete case analyses and an additional analysis of risk factors for presenteeism and absenteeism, with influenza vaccination status forcibly included in the model.All analyses were conducted with SAS software, version 9.4 (SAS Institute).

Demographical data
From 2016 to 2019, we obtained informed consent and enrolled a total of 2,637 HCP (Figure 1).After excluding 132 (5.0%) HCP without baseline data or surveillance data, 2,505 HCP remained in the analytic dataset completing active surveillance for a median of 100% (interquartile range (IQR): 87-100) of influenza season weeks; 1,242 (49.6%)HCP participated during a single influenza season, 963 (38.4%) in two seasons and 300 (12.0%) in all three seasons.The median age of the HCP at enrolment was 41 years (IQR: 33-51), 70.1% self-identified as female, 86.5% as non-ultraorthodox Jewish, 11.5% as Arab, 2.0% as ultra-orthodox Jewish, and 50.3% as being of high socioeconomic status (Table 1).Approximately one in four (n = 647; 25.8%) HCP had one or more pre-existing medical conditions at enrolment documented by electronic medical records.Most HCP were nurses (n = 1,426; 56.9%), followed by physicians (n = 630; 25.1%) and allied personnel (e.g.medical assistants and support personnel) (n = 449; 17.9%).Less than half (48.7%) of the HCP had received the current season's influenza vaccine during the enrolment year.

Clinical presentation and laboratory results of acute respiratory infections
In total, HCP developed 3,202 ARI episodes (cough, feverishness, rhinorrhoea or body aches) between 2016 and 2019 and had a median of one ARI episode per person-season (IQR: 0-1) (Table 2, Figure 2).The HCP provided respiratory swabs during 2,534 (79%) episodes of ARI and reported data on presenteeism and absenteeism in 2,655 (83%) episodes of ARI.The most common reason for not providing a swab was that participants could not self-collect a swab within 7 days of illness onset.The mean time from symptom onset to swab collection was 4 days (IQR: 2-5).Of the 2,534 ARI episodes with specimens collected, 206 (8%) tested positive for influenza and 107 (4%) tested positive for RSV by RT-PCR.Of the influenza-positive specimens, 34 were collected during the 2016/17 season, all of which were A(H3N2) infections, 102 were collected during the 2017/18 season, of which 72% were influenza B/ Yamagata and 28% were influenza A viruses (A(H1N1) pdm09 and A(H3N2) subtypes), and 70 specimens were collected during the 2018/19 season, of which 66% were influenza A(H3N2), 31% were A(H1N1)pdm09 and 3% were unsubtyped influenza A virus.Less than 2% of 313 influenza-or RSV-positive specimens were codetections (one (0.3%) influenza A(H3) and A(H1)), four (1%) influenza and RSV).
When we used person-time as a denominator in sensitivity analyses, findings on relative rates of ARI and influenza-or RSV-associated ARI were similar.Complete case analyses indicated consistent point estimates with wider confidence intervals because of the smaller analytic sample.Including influenza vaccination status in the model assessing risk factors for presenteeism and absenteeism did not significantly affect the estimates.The results of these sensitivity analyses are available in the supplementary material.
Among HCP experiencing influenza-associated ARIs, absenteeism was reported in 60% (95% CI: 52-67) of the episodes.The incidence of absenteeism during an influenza-associated ARI was 4.

Discussion
Influenza-and RSV-associated ARI were common among HCP in two large Israeli hospitals and frequently associated with presenteeism and absenteeism; these findings provide additional evidence of the potential value of measures to decrease respiratory infections among HCP, such as improving influenza vaccination coverage, optimising infection prevention and control and encouraging sick HCP to stay home to reduce the incidence of ARI and thereby decrease the risk of in-hospital transmission of viruses to staff and patients.While the incidence of RT-PCR-confirmed influenza illness among unvaccinated HCP was 9.1 per 100 person-seasons, the incidence more than doubled when combined with serological evidence of infection.These high rates of influenza among unvaccinated HCP are consistent with results from a recent systematic review, where the incidence of influenza illness and influenza infection among HCP was 7.5 (95% CI: 4.9-11.7)and 18.7 (95% CI: 15.8-22.1),respectively [2].
Although influenza viruses were the most frequently detected viruses, RSV infection also caused many ARI episodes among HCP.The risk of RSV we observed was consistent with results among HCP working in a hospital paediatrics department in California where approximately one in 20 HCP developed RSV illnesses: 5% among HCP who used personal protective equipment and 61% among HCP who did not [23].While RSV vaccines are approved in the European Union for pregnant women and adults aged > 60 years and in Israel for adults aged > 60 years [24], our findings of high RSV incidence, combined with the occupational risk while caring for ill patients [23,25], suggest that HCP may also be an important population to immunise against RSV with currently licensed products or others in development [26,27].
We found presenteeism was very common; HCP worked at least 1 day while ill during nine of 10 ARI episodes.A previous study of HCP in this same cohort found that high rates of presenteeism may be related to a strong personal work ethic and an institutional culture that discourages taking sick leave [3].High rates of presenteeism among HCP have also been described elsewhere [28,29].During the influenza season, 94.6% of HCP in Canada worked at least 1 day while ill with ARI, and this happened more frequently in the absence of paid sick leave [23].In the TransFLUas influenza transmission study, 67.9% of HCP with laboratory-confirmed influenza at the University of Zurich worked while ill [30].While age and provider role have not been identified in other cohorts at our study sites as risk factors for presenteeism, older HCP and those regularly working in the surgery department seemed more reluctant to stay home while ill.Healthcare personnel who worked while ill with influenza also have been shown to infect co-workers and vulnerable patients [29,31].The risk of transmission is probably highest during the first days of illness, when people are most likely to shed viruses.Persistent ARI symptoms could also impair HCP's ability to competently perform their duties while ill.The United States Centers for Disease Control and Prevention recommends that HCP stop patient care, don a mask and notify a supervisor when ill [32].
We also found that workplace absenteeism was common during ARI, as more than one in three ARI episodes resulted in missed workdays or > 23,000 h of lost work among our cohort of HCP.An association between ARIs and absenteeism has been observed previously [33].In Italy, HCP missed > 11,000 working days per year, resulting in an annual cost to society of ca EUR 1.7 million because of influenza illnesses [34].A healthy workforce helps ensure that healthcare systems are resilient.The work absences among HCP in Italy occurred during annual influenza epidemics, periods of time when healthcare systems need staff for surge capacity.Such potential erosion in the pool of healthy HCP can be even more problematic during a pandemic.
While a recent systematic literature review found that HCP who received an influenza vaccine had on average ca 64% (RR = 0.36; 95% CI: 0.25-0.54)lower risk of influenza virus infection and influenza-associated absenteeism compared with unvaccinated HCP [35], vaccines may be less effective in preventing mild illness during certain epidemics and among persons repeatedly exposed to influenza antigens.There may also be bias by indication, where persons who selfidentify as being at higher risk of ARI get vaccinated more frequently than others, hoping to protect themselves against influenza.In our cohort, standard dose influenza vaccines were not effective during the period 2016 to 2019 at preventing influenza ARI among HCP at Soroka and Rabin Medical Center [21].However, new enhanced influenza vaccines that have recently become more widely available may offer better protection: Recent clinical trials suggest that cell-based influenza vaccines may provide superior immunogenicity among HCP, compared with egg-based influenza vaccines [36]; other clinical trials are ongoing among HCP to explore whether high-dose or adjuvanted influenza vaccines could provide superior protection to HCP [37].
Infection control practices such as vaccination, frequent handwashing, disinfection of equipment and the proper use of personal protective equipment can prevent nosocomial infections [32].Less than half of the Soroka and Rabin Medical Center HCP received the influenza vaccine each season.Additional efforts at healthcare facilities to increase influenza vaccination uptake among HCP could be undertaken to address these low coverage rates.Sick HCP should also stay at home when they are sick to reduce the risk of infecting colleagues and vulnerable patients [33].Previous research in Israel has identified several reasons why HCP choose to work while sick, including the belief that influenza is not serious enough to prevent working [3].In addition to efforts aimed at increasing vaccination uptake, hospitals could offer paid sick leave to discourage presenteeism or explore the cost-effectiveness of antiviral treatment within 48 h of illness onset to decrease illness duration and the risk of complications [38].
Our study had notable strengths.We prospectively followed HCP twice a week in two hospitals during three seasons with relatively high active surveillance completion, and nearly four of five symptomatic HCP selfcollected their swabs.Self-collection has been shown to be a reliable diagnostic method for influenza with relatively high sensitivity and specificity [16].While we relied on RT-PCR-confirmed influenza-like illness to quantify influenza incidence in previous cohorts [20], we used a sensitive case definition of acute respiratory infection and obtained pre-and post-season serology to improve the probability of identifying asymptomatic infection.Data on presenteeism and absenteeism were identified from a combination of illness surveys and data from hospital human resources departments, making our findings more robust.
Our study had limitations.Fewer HCP were enrolled in the 2016/17 influenza season than in the other two seasons, resulting in fewer swabs tested that year.However, the percentage of participants who reported ARI and had swabs collected was similar throughout all three seasons.The study occurred before the COVID-19 pandemic and HCP attitudes about working while sick may have changed since the pandemic.While our findings about presenteeism and absenteeism present robust pre-pandemic data, rates of presenteeism and absenteeism should be re-evaluated because of potentially altered attitudes and policies, for example, about masking and working while sick.Influenza-associated ARI episodes may have been missed when swabs were not collected or collected too late [15].However, we used multiple imputation to address the potential underestimation of influenza incidence because of missed detections.Incidence of RSV-associated ARI may not fully reflect RSV incidence and risk among HCP in our study because active surveillance was only conducted during the influenza season which can occur after peak RSV circulation in Israel [11].While we used a sensitive ARI case definition, some pauci-symptomatic illnesses among persons infected with influenza may have been missed [20].If influenza infections occurred early in the season, it is possible that they would have been identified as seronegative at the end of the season and incorrectly classified as uninfected if there had been considerable waning of their antibody titres [39].

Conclusion
We found high incidence of acute respiratory illness and influenza and RSV infections among HCP at two large hospitals in Israel during three influenza seasons.The HCP commonly reported workplace presenteeism and absenteeism.Improving influenza vaccination coverage, considering the introduction of RSV vaccines among HCP, optimising hospital infection prevention and control measures to reduce the burden of ARI (e.g.frequent hand hygiene, use of gloves, gowns, and face masks for patients under droplet precautions, isolation or cohorting of influenza or RSV cases, caution when performing aerosol-generating procedures, environmental surface cleaning etc.), and encouraging sick HCP to stay at home are all important strategies to reduce the incidence of ARI among HCP and decrease the risk of in-hospital transmission of viruses to staff and patients and optimise healthcare system resilience.Further studies are needed to examine strategies to optimise such interventions.

Figure
Figure 1Flowchart for recruitment of participants, study on respiratory infection and presenteeism/absenteeism among healthcare personnel, Israel, 2016-2019 influenza seasons (n = 2,637)

Figure 2
Figure 2Healthcare personnel with laboratory-confirmed influenza and respiratory syncytial virus-associated acute respiratory infections and percentage of positive samples, by epidemic week, Israel, 2016-2019 influenza seasons (n = 2,534 ARI episodes with swabs)

Number of bedrooms in the home
ARI: acute respiratory illness; Col%: column %; HCP: healthcare personnel; RSV: respiratory syncytial virus.a 1,242 HCP participated in one season only, 963 participated in two seasons, and 300 participated in all three seasons.b p value was calculated using univariate Poisson regression with robust sandwich variance estimator.c Two HCP did not report the number of children in their household in 2017.d At the beginning of each season, participants self-reported their overall health status.e Healthcare personnel were considered vaccinated if they had received an influenza vaccine before the peak of the influenza season.f Aerosol-generating procedures included collecting respiratory specimens or sputum, administering nebulisers, applying supplemental O2 through nasal canula or face masks, applying mechanical ventilation, performing intubations, suction, chest physiotherapy, bedside bronchoscopy, or manual ventilation, and inserting nasogastric tubes.Entries in bold indicate statistical significance.

Number of regularly performed aerosol-generating procedures (on average per shift) f
ARI: acute respiratory illness; Col%: column %; HCP: healthcare personnel; RSV: respiratory syncytial virus.a 1,242 HCP participated in one season only, 963 participated in two seasons, and 300 participated in all three seasons.b p value was calculated using univariate Poisson regression with robust sandwich variance estimator.c Two HCP did not report the number of children in their household in 2017.d At the beginning of each season, participants self-reported their overall health status.e Healthcare personnel were considered vaccinated if they had received an influenza vaccine before the peak of the influenza season.f Aerosol-generating procedures included collecting respiratory specimens or sputum, administering nebulisers, applying supplemental O2 through nasal canula or face masks, applying mechanical ventilation, performing intubations, suction, chest physiotherapy, bedside bronchoscopy, or manual ventilation, and inserting nasogastric tubes.Entries in bold indicate statistical significance.

Table 3
Cumulative incidence and relative rate of acute respiratory illness and RT-PCR-confirmed influenza or respiratory syncytial virus infection among healthcare personnel by sociodemographic and occupational factors, Israel, 2016-2019 influenza seasons (n = 2,505) Cumulative incidence and RR were estimated using multivariable Poisson regression with robust sandwich variance estimator.Entries in bold indicate statistical significance. a

Table 4
Presenteeism and absenteeism rates and cumulative incidence of acute respiratory infections per 100 person-seasons, Israel, 2016-2019 influenza seasons (n = 2,505) ARI: acute respiratory illness; CI: confidence interval; RSV: respiratory syncytial virus.a For the presenteeism/absenteeism rate, 95% Clopper-Pearson confidence intervals were calculated.Cumulative incidence was estimated using multivariable Poisson regression with robust sandwich variance estimator.

Table 5
Risk factors for acute respiratory illness associated presenteeism and absenteeism among healthcare personnel, Israel, 2016-2019 influenza seasons (n = 3,202 episodes) Odds ratios were estimated using multivariable logistic regression with robust sandwich variance estimator to account for healthcare personnel reporting more than one illness episode.Entries in bold indicate statistical significance.
CI: confidence interval; aOR: adjusted odds ratio.a